betadex and Leukemia--Myeloid--Acute

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. HP-β-CyD has recently been approved for the treatment of Niemann-Pick Type C disease, a lysosomal lipid storage disorder, and is used in clinical practice. Since cholesterol accumulation and/or dysregulated cholesterol metabolism has been described in various malignancies, including leukemia, we hypothesized that HP-β-CyD itself might have anticancer effects. This study provides evidence that HP-β-CyD inhibits leukemic cell proliferation at physiologically available doses. First, we identified the potency of HP-β-CyD in vitro against various leukemic cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia (CML). HP-β-CyD treatment reduced intracellular cholesterol resulting in significant leukemic cell growth inhibition through G2/M cell-cycle arrest and apoptosis. Intraperitoneal injection of HP-β-CyD significantly improved survival in leukemia mouse models. Importantly, HP-β-CyD also showed anticancer effects against CML cells expressing a T315I BCR-ABL mutation (that confers resistance to most ABL tyrosine kinase inhibitors), and hypoxia-adapted CML cells that have characteristics of leukemic stem cells. In addition, colony forming ability of human primary AML and CML cells was inhibited by HP-β-CyD. Systemic administration of HP-β-CyD to mice had no significant adverse effects. These data suggest that HP-β-CyD is a promising anticancer agent regardless of disease or cellular characteristics.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antineoplastic Agents; Apoptosis; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Cholesterol; Colorimetry; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; G2 Phase Cell Cycle Checkpoints; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lung; M Phase Cell Cycle Checkpoints; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Signal Transduction; Transplantation, Heterologous

CD44 is a cell surface antigen expressed on acute myeloid leukemia cells and is used as a marker to isolate leukemia stem cells. CD44 ligation with the antibody A3D8 has been found to induce apoptosis in human acute promyelocytic leukemia (APL) cells via activation of caspase-8. The mechanism of A3D8-induced caspase-8 activation was studied in APL NB4 cells. A3D8 induces lipid raft clustering which causes Fas aggregation as determined with a confocal microscope. A3D8-induced apoptosis is abrogated by the lipid raft disrupting agent methyl-β-cyclodextrin and the caspase-8 inhibitor Z-IETD-fmk. Western blot analysis reveals that A3D8 binds to the standard form of CD44 (CD44s). HL-60 cells without detectable CD44s protein are not responsive to A3D8-induced apoptosis. SKNO-1 cells containing higher level of CD44s protein are more sensitive to A3D8-induced apoptosis than NB4 cells. These results indicate that A3D8 induces apoptosis in leukemia cells through caspase-8 activation by binding to CD44s protein and inducing lipid raft clustering.

Topics: Antibodies, Monoclonal; Apoptosis; beta-Cyclodextrins; Caspase 8; Cell Line, Tumor; fas Receptor; HL-60 Cells; Humans; Hyaluronan Receptors; Hyaluronic Acid; Leukemia, Myeloid, Acute; Lipid Metabolism; Oligopeptides